Dispensing unit for therapeutic agents



W. A. WINSTEN DISPENSING UNIT FOR THERAPEUTIC AGENTS Filed April 5, 1949 July 31, 1951 INVENTO WALTER A. WINS Fatented July 31 1951 DISPENSING UNIT FOR THERAPEUTIC AGENTS Walter A. Winston, Forest Hills,-N. Y., assignor to w Food Research Laboratories, Inc., Long Island City, N. Y., a corporation of New York Application April 5, 1949, Serial No. 85,584

8 Claims. (01. 167-63) This invention relates to dispensing units adapted for the administration of therapeutic agents; and in particular is directed to units for dispensing an hydrophilic ointment which comprises penicillin, or other therapeutic agents unstable in aqueous media.

It is well known, for example, that penicillin in the form of various salts, such as the potassium, sodium, or calcium salt is unstable in aqueous media.

Such penicillin salts also are not Stable when embodied in various hydrophilic ointment bases even if they contain but little or nowater. The chemical groups such as the alcohol group or the carboxyl group and the like which confer hydrophilic properties to an ointment also contribute to the instability of the penicillin salt. As a consequence of such properties,- it is not possible to prepare stable hydrophilic penicillin ointments. It has been the practice, in view of such instability, to employ hydrophobic ointment bases in which either crystalline or amorphous salts of penicillin are suspended, since it has been found that crystalline penicillin salts embodied in a hydrophobic base are quite stable.

However, it is Well known that hydrophilic ointments are to be preferred over hydrophobic ointments by reason of the fact that they release penicillin more rapidly and in greater concentrations to affected or diseased tissues. A further advantage resides in the fact that hydrophilic ointments may more readily be removed by flushing with water or saline when such removal is desired.

In using the therapeutically more desirable hydrophilic ointments, it is necessary to prepare them as needed and promptly to use them after preparation. For this reason it has not been practicable heretofore to distribute or store. hydrophilic penicillin ointments on a commercial basis because of the necessity for continuous refrigeration which itself is not conducive to the stability of certain types of ointment bases.

Accordingly, it is one of the principal objects of this invention to provide a hydrophilic ointment base preparation comprising penicillin salts and/or other therapeutic agents which are unstable in the presence of water, the therapeutic agent being present in such form that its stability is preserved over an extended period of time.

In its fundamental aspects this invention provides a dispensing unit comprising a hydrophilic ointment and a therapeutic agent unstablein the presence of water, so disposed with respect to each other that they maybe mixed bythe patient immediately prior to the application the drug. The unit consists essentially of a dual container, the outer phase holding the hydrophilic ointment base and a separately disposed inner phase holding the relatively small amount of the therapeutic agent, the two phases being kept sealed and apart from each other.

The objects and advantages of this invention will be more fully understood from the following detailed description thereof taken in connection with the accompanying drawing wherein:

Fig. 1 is a top plan view of a dispensing unit showing a form of this invention.

Fig. 2 is a cross-sectional view of the dispensing unit illustrated in Fig. 1 and taken on the line 22 thereof.

In the drawings the numeral l0 designates a heat and pressure scalable envelope of a plastic film, as, for example, compounded from polyvinyl chloride, rubber, and plasticizers, or any other appropriate durable and flexible material. Set within the envelope I0 is a hydrophilic ointment base M the composition of which is hereinafter described. Within the matrix of the ointment base it there is located a small rupturable casing, as for example a capsule E6 or the like. The capsule I6 is filled with a hydrophobic material, such as an oil, fat, or wax, as for example, sesame oil or other appropriate material l8. If desired, the oil l8 may be thickened or rendered more viscous by hydrogenation or by the addition thereto of metallic soaps. There is suspended in the oil any stable salt of penicillin, such as the crystalline sodium, potassium, or procaine salts, or the amorphous salts thereof, such as the calcium salt. The penicillin saltis thus suspended in the hydrophobic material contained Within theinner small capsule.

It willbe observed that such structure that houses the penicillin salt suspended in the oilor other appropriate material of hydrophobic nature provides a dispensing unit in which the penicillin is maintained in stable condition.

When it is desired to apply the drug in the form of the ointment containing the same,'theprocedure is as follows: The physician, nurse, or

patient, holds the unit between the fingers and exerts pressure on the flexible outer wall :2 until the wall of the contained casing or capsule l6 is ruptured. Upon such rupture the penicillin suspended in the oily vehicle is brought into direct contact with the hydrophilic ointment M. The unit is then manipulated until the penicillin is thoroughly distributed throughout the hydrophilic ointment.

The ointment itself comprises as a main constituent a wetting agent which imparts hydrophilic properties thereto. This wetting agent also solubilizes or readily disperses the oil or the hydrophobic material used to maintain the penicillin suspended in stable condition in the internal casing 16. The manipulation of the durable. flexible, outer plastic membrane or the unit may easily be efiected so that the penicillin is rapidly distributed throughout the matrix of the hydrophilic ointment and thepenicillin ointment thus made ready for application.

It will be observed that this invention utilizes the known stability of penicillin when suspended in a hydrophobic medium; and taking ia'dvan tage of such stability allows for the-"easy incorporation of the penicillin, so suspended, into a hydrophilic medium that also possesses the property of instantly dispersing the hydrophobic suspending agent, thus bringing about the intimate contact of the penicillin with the hydrophilic medium. If 'the latter contains a small amount of water, the penicillin will dissolve during manipulation of the unit.

I-have found that a hydrophilic ointmentbase containing principally a dispersing agent such as Tween 20 (a ,polyoxylethylene derivative of sorbitan monolaurate) :is effective in-solubilizing or dispersing hydrophobic penicillin compounds.

In place of Tween 20 there can-be used Tween 40 or Tween fio, which are respectively :the :monopalmitate and monostearate analogues.

A typical formulation of the hydrophilic ointment may bemade as follows:

8igrams=ofstearic acid and-25 gramsof Tween 20 are heated so as to obtain a solution thereof. There are then added :to such solution 6.5 ml. of water or buffer (0.2 M phosphate bufier, pH 6.0) withstirring. On cooling the ointment base sets. The'stearic acid imparts body to the ointment. In place of the stearic acid Carbowax 4,000 (a polyethylene glycol of average molecular weight, 4,000) may be used. It is unnecessary-to add water'to the above formulation.

Other ointment bases similar in character to theabov-e are effective .for the-process, so long as they contain a principal amount of a wetting agent which confers hydrophilic properties and also serves to solubilize or disperse the hydrophobic material used for suspending the penicillin salt. It has been found convenient to fill the plastic dispensing unit with an amount :of, the hydrophilic ointment base, and to use asufiicient amount'of .penicillin within-thelinner rupturable casing or capsule, toprovide for one dose or application. I

In its most generalaspect, .thisinvention comprises a structure whereby penicillin, or (other drug unstable-in aqueous.media,.is suspended in a hydrophobic medium, the suspension being mechanically separated, by a suitable rupturable membrane, from a hydrophilic ointment base. The unit of such physical structure that the aforesaid membrane maybe convenientlyruptui'ed by manipulating theouter wall of the .unit so as to bring the hydrophobic suspension'ofithe penicillin into intimate contact withhydrophilic base, the base being of a -.type which has the property of solubilizing or dispersing the hydro phobic suspending agent: so as readily to provide for Ithe incorporation of .the penicillin in ithc main body of the hydrophilicointment.

, It will beapparent that modifiedformsof such units may be used, as for example, :a'collapsible outer metal tube partly filled with=awsuitable aliv .philic bases.

drophilic ointment within which is disposed at rupturable cartridge containing a suspension of penicillin in a hydrophobic agent.

Among the various therapeutic agents which are unstable in the presence of water and, accordingly, can be put up only in hydrophobic materials in order to insure the shelf life thereof are: peni'cillin, bacitracin, and -.penicillin amide. The antibiotic bacitracin, a peptide-like substance, is also unstable in water or in hydro- However, it is stable so long as it is maintained in contact with hydrophobic media. The amide of penicillin is an antibiotic derivative of penicillin also unstable in water.

It will be understood that the foregoing description is but illustrative of the means of accomplishing this invention and accordingly the appended claims are to be construed as defining the invention within the full spirit and scope thereof.

I claim:

1. Adispensing unit adapted for theadrninis tration of a hydrophilic ointment embodying ia drugunstablein aqueous media, comprising: an envelope; a hydrophilic ointment'contained within said envelope; a rupturable casing disposed within the envelope, said rupturable casingtcontaining a hydrophobic material .having. .distributed therethrough adrug unstableinaque'ous media whereby the manipulation of the:envelopeeffectuates the rupture :of the casing and brings about the'distribution'of the :drug in the hydro philic ointment.

2. A dispensing unit iadaptedifor the administration of .a hydrophilic ointment embodying -'a drug unstable :in aqueous :media, which comprises: a tough, flexible'outer envelope; a hydrophilic ointment comprising a wetting agent, said ointment being contained 'within the envelope; a .rupturable easing disposed within the outer envelope; saidzcasing containing a-hydrophobic material havingdistributed therethroug'h a drug unstable in aqueous media whereby the manipulationof the envelope 5 efieotuates the rupture of the casing and brings about the distribution-of theldrug in theihydrophilic ointment.

3. .-A dispensing unit adapted for the admin istration of a hydrophilic ointment embodying a drug unstable in aqueousamedia, whiclr 'com prises: a .durable flexible outer envelopeya hydrophili'c @oininn'ent, said ointment being contained within the envelope; a'rupturable-casing disposed within the envelope; said casingcontaining a penicillin salt distributed in a hydro phobic medium whereby themanipulationnf the outer :envelope --effectu'ates the ruptureof the casing and brings about the distribution of the penicillin salt .in .the.hydrophilicrointment.

4. A dispensing unit :adapted for the administration of a hydrophilicointment embOdying a drugunstable in aqueous media, which comprises? a durable .flexible outer envelope; a hydrophilic ointment comprising a wetting agent contained within the outer envelope; ;a .rupturable casing containing a .hydrophobic material having distributed therethrough a salt of penicillin, said casing being disposed within theeouter envelope whereby manipulationiof the envelope effectuates the rupture of the casing J. and brings about the distribution of thejpenicillin in.=hydrophilio'oint-- ment.

5. A dispensing .unit adapted for :the administration of .a hydrophilic ointment embodying-' a drug unstable inaqueous mediaqwhich comprises a durable .ifiexibie outer envelope; a hydmphilic ointment, said ointment being contained within the envelope; a rupturable casing disposed within the envelope; said casing containing penicillin amide distributed in a hydrophobic medium whereby the manipulation of the outer envelope effectuates the rupture of the casing and brings about the distribution of the penicillin amid in the hydrophilic ointment.

6. A dispensing unit adapted for the administration of a hydrophilic ointment embodying a drug unstable in aqueous media, which comprises: a durable flexible outer envelope; a hydrophilic ointment comprising a wettin agent contained within the outer envelope; a rupturable casing containing a hydrophobic material having distributed therethrough penicillin amide, said casing being disposed within the outer envelope whereby manipulation of the envelope efiectuates the rupture of the casing and brings about the distribution of the penicillin in hydrophilic ointment.

7. A dispensing unit adapted for the administration of a hydrophilic ointment embodying a drug unstable in aqueous media, which comprises: a durable flexible outer envelope; a hydrophilic ointment, said ointment being contained within the envelope; a rupturable casing disposed within the envelope; said casing containing bacitraoin distributed in a hydrophobic medium whereby the manipulation of the outer envelope effectuates the rupture of the casing and brings about the distribution of the bacitraoin in the hydrophilic ointment.

distributed therethrough bacitracin, said casing being disposed within the outer envelope whereby manipulation of the envelope eflectuates the rupture of the casing and brings about the distribution of the baoitracin in hydrophilic ointment.

WALTER A. WINSTEN.

REFERENCES CITED The following references are of record in the file bf this patent:

UNITED STATES PATENTS Number Name Date 683,994 Schirmer Oct. 8, 1901 1,077,835 Kelly Nov. 4, 1913 1,960,858 Strauch May 29, 1934 2,100,456 Spensley Nov. 30, 1937 2,176,923 Nitardy Oct. 24, 1939 2,184,152 Safflr Dec. 19, 1939 2,275,567 Smith Mar. 10, 1942 2,469,204 Peters May 3, 1949 FOREIGN PATENTS Number Country Date 35 ,651 Fran e Juli .224 905 

1. A DISPENSING UNIT ADAPTED FOR THE ADMINISTRATION OF A HYDROPHILIC OINTMENT EMBODYING A DRUG UNSTABLE IN AQUEOUS MEDIA, COMPRISING: AN ENVELOPE; A HYDROPHILIC OINTMENT CONTAINED WITHIN SAID ENVELOPE; A RUPTURABLE CASING DISPOSED WITHING THE ENVELOPE, SAID RUPTURABLE CASING CONTAINING A HYDROPHOBIC MATERIAL HAVING DISTRIBUTED THERETHROUGH A DRUG UNSTABLE IN AQUEOUS MEDIA WHEREBY THE MANIPULATION OF THE ENVELOPE EFFECTUATES THE RUPTURE OF THE CASING AND BRINGS ABOUT THE DISTRIBUTION OF THE DRUG IN THE HYDROPHILIC OINTMENT. 